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Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease.

Abstract：

:It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-β (Aβ)-induced apoptosis. Therefore, blocking GSK3β-induced Drp1 phosphorylation may be an effective way to protect neurons from Aβ toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3β-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aβ-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aβ burden and rescued the memory deficits in AD transgenic mice. Although Aβ has multiple targets to exert its neurotoxicity, our findings suggested that GSK3β-induced mitochondrial fragmentation was, at least partially, mediated by Aβ toxicity and contribute to the pathogenesis of AD. Taken together, GSK3β-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD.

journal_name

Neurobiol Aging

journal_title

Neurobiology of aging

authors

Yan J,Liu XH,Han MZ,Wang YM,Sun XL,Yu N,Li T,Su B,Chen ZY

doi

10.1016/j.neurobiolaging.2014.08.005

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

211-27

issue

1

eissn

0197-4580

issn

1558-1497

pii

S0197-4580(14)00518-1

journal_volume

36

pub_type

杂志文章

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